Translational research, bringing new laboratory findings quickly to improve prevention, treatment, quality of life, and survival for breast cancer patients, has been the focus of the team now forming the Baylor Breast Center for 25 years. During the first ten years of our SPORE, our tumor bank which made much of this rapid translation possible became a national resource, while basic cell and molecular biology research suggested new clinical implications for endocrine and chemo-therapy resistance, breast cancer prevention, metastasis, development of premalignant lesions, and roles for tumor suppressor genes BRCA-1 and -2 in DNA repair. Developmental projects ranged even further in seeking new translational possibilities. In this SPORE renewal, we build on the results developed in our earlier work and on new findings and new technologies, in several directions. (1) Compelling new data indicates that cross-talk from growth factor and stress pathways to the estrogen receptor and its co-activators may lie at the root of clinical resistance to tamoxifen, and suggests feasible clinical interventions. We will lay the preclinical groundwork for definitive trials and examine in clinical specimens the prognostic and predictive value of key intermediates from these pathways. (2) Our gene expression array studies offer the promise of a rational risk classification of DCIS. We will assess key markers indicated by these studies on a unique series of DCIS specimens, to evaluate their potential to predict progression to invasive cancer. (3) Tamoxifen can prevent ER-positive breast cancer in many high-risk women, but does nothing against the emergence of ER-negative disease. Based on ongoing treatment studies plus our own laboratory data, we now propose preclinical studies and an early clinical trial of the receptor tyrosine kinase inhibitor Iressa in chemoprevention of breast cancer in women at risk. (4) Our discovery that a single hypersensitive estrogen receptor mutant is found in many hyperplasias and in most node-positive breast cancers, but not in normal tissue, suggests that this mutant could be not only a powerful risk indicator but a uniquely specific treatment target. We will explore both possibilities. (5) Our preliminary expression array data in responders vs. non-responders to neoadjuvant Taxotere implies that the gene expression profile might strongly predict clinical sensitivity or resistance. We will test in a randomized trial the ability of expression profiles to distinguish Taxotere from AC sensitivity, and confirm markers from these profiles in sets of retrospective clinical specimens. (6) Although important parts of our unique breast Tissue Resource were lost in last year's floods, much remains, and we propose important new accessions to further enhance this critical resource. (7) Pathology, Biostatistics, and Administrative Cores will also support key aspects of the proposed work. (8) Our highly successful Developmental Projects Program and Career Development Program will continue to encourage new ideas and new investigators in translational breast cancer research.